Susceptibility to and stratification for monoaminergic antidepressants

Abstract

The present invention relates to a method for predicting the non-response or response to a monoaminergic antidepressant of a patient to be treated with a monoaminergic antidepressant comprising the steps: (i) determining the DNA-methylation status of a brain-derived neurotrophic factor (BDNF)-gene promoter in a sample of said patient; (ii) attributing a hypomethylation of said BDNF-gene promoter to the non-response to a monoaminergic antidepressant of said patient; and (iii) attributing normal methylation or hypermethylation of said BDNF-gene promoter to the response to a monoaminergic antidepressant of said patient. Furthermore, a kit and the use of a kit in said method is disclosed.

The invention claimed is: 
     
       1. A method of determining the hypomethylation status of a CpG island in human brain-derived neurotrophic factor (BDNF)-gene promoter in a patient, wherein said method comprises:
 (a) performing a DNA methylation status assay to detect the level of DNA-methylation of CpG-87 of exon-IV of the human BDNF-gene promoter in a sample derived from the patient, 
 (b) assaying for the hypomethylation status of CpG-87 by determining the methylated cytosine (C) fraction of CpG-87; 
 wherein a hypomethylated CpG-87 is less than 0.05 and 
 wherein said patient is suffering from depression, major depressive disorder, mild depression, panic disorder, social anxiety disorder, social phobia, bulimia nervosa, obsessive-compulsive disorder, post-traumatic stress disorder, or generalized anxiety disorder. 
 
     
     
       2. The method of  claim 1 , wherein said patient is reported as a non-responder to a monoaminergic antidepressant. 
     
     
       3. The method of  claim 1 , wherein a methylated C fraction of 0.05 or greater at CpG-87 in the sample is reported and said patient is reported as a responder to a monoaminergic antidepressant. 
     
     
       4. The method of  claim 3 , wherein the method further comprises administering to the patient having a methylated C fraction of 0.05 or greater at CpG-87 a monoaminergic antidepressant selected from a serotonin reuptake inhibitor (SSRI), a selective serotonin and noradrenalin reuptake inhibitor (SNRI), a selective noradrenaline and dopamine reuptake inhibitor, a selective norepinephrinedopamine reuptake inhibitor, a monoamine oxidase inhibitor, a tricyclic antidepressant, or monoaminergic antidepressants. 
     
     
       5. The method of  claim 3 , wherein the method further comprises administering to the patient having a methylated C fraction of 0.05 or greater at CpG-87 a monoaminergic antidepressant selected from venlafaxin, sertralin, mirtazapin, escitalopram, citalopram, fluoxetine, paroxetin, duloxetin, bupropion, amitriptylin, clomipramin, trimipramin, tranylcypromin or agomelatine. 
     
     
       6. The method of  claim 1 , wherein the DNA methylation status assay is selected from bisulfite sequencing, pyrosequencing, MALDI-TOF, methylation sensitive enzymatic digestion, or qMSP. 
     
     
       7. The method of  claim 1 , wherein the method is performed before administration of a monoaminergic antidepressant. 
     
     
       8. The method of  claim 1 , wherein the sample is obtained from blood, serum, plasma, saliva, sputum or cerebrospinal fluid. 
     
     
       9. The method of  claim 1 , wherein the method further comprises determining the DNA-methylation status of at least one additional CpG island of human BDNF gene promoter selected from CpG−148, CpG−111, CpG+18, CpG−66, CpG−58, CpG−35, CpG−39, CpG−24, CpG−11, CpG+20, CpG+36, CpG+42, CpG+51, and CpG+54. 
     
     
       10. The method of  claim 9 , wherein the method further comprises determining the methylated C fraction of at least one additional CpG island of human BDNF gene promoter selected from CpG−148, CpG−111, CpG+18, CpG−66, CpG−58, CpG−35, CpG−39, CpG−24, CpG−11, CpG+20, CpG+36, CpG+42, CpG+51, and CpG+54. 
     
     
       11. The method of  claim 10 , wherein the CpG island is further reported to be hypomethylated if the methylated C fraction of the CpG island is selected from:
 a. CpG−148 of less than 0.10; 
 b. CpG−111 of less than 0.12; 
 c. CpG+18 of less than 0.03; 
 d. CpG−66 of less than 0.05; 
 e. CpG−58 of less than 0.12; 
 f. CpG−35 of less than 0.04; 
 g. CpG−39 of less than 0.05; 
 h. CpG−24 of less than 0.02; 
 i. CpG−11 of less than 0.02; 
 j. CpG+20 of less than 0.02; 
 k. CpG+36 of less than 0.02; or 
 l. CpG+42 of less than 0.26. 
 
     
     
       12. The method of  claim 1 , wherein the method comprises determining the DNA-methylation status of CpG−87, CpG−66 and CpG−58. 
     
     
       13. The method of  claim 1 , wherein the DNA methylation status assay comprises contacting the DNA in the sample with bisulfite or sodium bisulfite.